The present invention relates to a process for the production of a flat administration form having a drug portion capable of being dosed or of a flat-shaped device for the dosable release of volatile substances, such as aromatic substances, to the ambient air by using high-volatile or thermolabile dosing media in liquid or semisolid state as the ingredients of the administration form or of the device by means of printing processes, wherein a flowable preparation of the ingredients is knife-coated in a measured amount into at least one volumetrically defined sink of a flat printing block. In the production of substantially flat-shaped administration forms or devices, this process is to permit the amount of liquid active substances, liquid active substance preparations, and/or liquid active substance/adjuvant mixtures to be dosed to the other components of the administration form or device in an accurate and superficially even manner.
Such flat-shaped administration forms may, for example, be transdermal therapeutic systems, transmucosal systems, dermal, i.e., only topically effective, systems, but also those to be administered orally, such as sublingual tablets or sublingual wafers. The process is of particular value in the production of transdermal or dermal systems of the matrix type and membrane systems with a fixed reservoir.
Since the function of such transdermal or dermal therapeutic systems and the materials required for their production are well known to the skilled artisan, it is only mentioned in a few words that the active substance(s) is/are present in the usually self-adhesive systems in an at least partially dissolved form; and after application of the system on the skin they diffuse from the system into the skin, developing a local or systemic effect.
The present invention will be illustrated in the following with reference to the accompanying drawings by comparison with the state of the art.
The most simple construction is that of known, single-layer matrix systems. According to FIG. 1 they may consist of an impermeable backing layer 3, a self-adhesive matrix layer 2, and a removable protective layer 1.
The matrix layers (and the same applies to reservoir layers of the above-mentioned membrane systems) are usually manufactured in such a manner that components of the matrix and active substances, dissolved in a solvent, are coated on a suitable sheet or film (removable protective layer 1), and that the solvents are removed in a drying process. This production method may cause considerable difficulties if ingredients are required that are either incompatible with the solvents or very temperature-sensitive; or if they have an excessively high vapor pressure at the drying temperature.
Examples of thermolabile active substances include, for example, vitamin D.sub.3 -derivatives; examples of active substances having an excessive volatility include the active substances nicotine or nitroglycerin, for example. Another important group of substances used for dermal or transdermal therapeutic systems are the so-called penetration enhancers. The function of these penetration enhancers is to facilitate the passage of active substances through the skin.
Examples of high-volatile penetration enhancers include, for example, terpenes (eucalyptol, camphor, etc.); esters (ethyl acetate, ethyl propionate, etc.); alcohols (ethanol, propanol, propanediol, etc.); or ketones (methyl hexyl ketone; methyl octyl ketone, etc.).
Incompatibilities between solvents and components must be expected whenever a chemical reaction may take place between them. For instance, alcohols are used for many adhesives; these may then react with active substances which have a free carboxyl group or an ester group in the form of an esterification or transesterification.
In order to avoid these difficulties, processes have been developed wherein a liquid preparation of the problematic substances is applied on a flat substrate at room temperature, and said substrate is then located between prefabricated layers of the administration form that is to be formed. The liquid preparation with all its diffusible components completely migrates into these layers within some hours or days. Such a substrate may consist, for example, of a paper film, a non-woven fabric, a textile fabric, or other absorbent materials. The most simple situation is given when a material (5) according to FIG. 2 which is impregnated with a liquid preparation is located between a laminate consisting of an impermeable backing layer (3) and a self-adhesive anchoring layer (6) and a second laminate consisting of a removable protective film (1) and another self-adhesive layer (4) contacting the skin.
Alternatively, the substrate to be impregnated may also be laminated on either of the self-adhesive layers 4 or 6, prior to application of the liquid preparation.
The finished systems (FIG. 3) are punched out of a large-area total laminate, for this reason it is advantageous--in case very expensive active substances or adjuvants, or active substances involving a great danger of misuse, e.g., narcotics, are used--to apply the liquid preparation in the form of patterns corresponding to the shape of the systems that are to be produced so that the resulting waste punchings are free from said substances.
U.S. Pat. No. 4,915,950 describes a method of producing such systems. Arbitrary dosing processes are generally summarized herein under the term printing process. The following are mentioned separately: gravure printing, extrusion coating, screen printing, spraying, and spread coating. However, none of the examples given herein exactly describe which special printing process was used for the respective production.
For this reason, it cannot be evaluated to what degree the employed production processes meet the demands to be made for drugs with respect to accuracy of dosage.
DE 35 31 795 A1 describes another example of a system wherein active substance-containing regions and active substance-free waste areas are applied on a carrier material and separated by punching subsequently.
It is said that an accurate dosage of the active substances can be achieved by means of exactly engraved or etched printing rolls or printing plates. The separation into active substance-free and active substance-containing zones is effected by means of printing methods which are not explained in greater detail-screen printing, flexographic printing, gravure printing, or noncontact printing processes, such as ink-jetting or spraying through nozzles and the like, are mentioned. However, there are no indications with respect to the way the known printing processes manage to keep to given accurate dosage quantities of active substances at defined concentrations per unit area. Apparently, this is not important because mothproof paper is concerned which releases an insecticidal aromatic substance to the ambient air over longer periods; in contrast to an administration form having skin contact, an exact concentration per unit area is not required.
OS 37 27 232 describes a special printing process, a so-called tampon printing process, for the active substance dosage in the production of transdermal or dermal systems.
Modern tampon printing processes have been known since 1968; a tampon printing unit is described in DE-OS 19 39 437, for example. Said printing technique is particularly suitable to print uneven surfaces because a deformable tampon transferring the printing medium adapts to the substrates to be printed.
In this process, the pattern to be printed is etched into a metal plate 10. The printing medium 12--referred to in the following description as dosing or metering medium--is transferred into the etched sink 14 (FIG. 4a), metered by means of knife coating (FIGS. 4b and c), subsequently taken up by the tampon 16 (FIGS. 4d and e), and transferred to the article 8 to be printed (FIG. 4f).
The disadvantage of this process is the fact that the transferred active substance quantities depend on a great variety of factors. Primarily, these are determined by the etched depth of the printing form; but also, for example, by the viscosity and cohesion of the metering medium, the adhesion of the metering medium to the plate material, and by the hardness and surface properties of the tampons that are used. For this reason, it may be difficult to coordinate these factors such that the desired measured weight is achieved and maintained over prolonged production periods. In particular if large areas are concerned and in case of a print image deviating from a circular geometry, it is very difficult to achieve an even area distribution of the metering medium. However, the even distribution of the dosing medium on the surface is of particular and decisive importance in the production of transdermal or dermal therapeutic systems.
In case of a dermal system, for instance, an irregular surface distribution of the active substance results in differently intensive actions over the complete application site; in case of a transdermal system the systemically available active substance amount may be determined by the active substance distribution. The concentration of the liquid or semisolid dosing medium in the administration form frequently influences the physical properties thereof. In case of dermal or transdermal systems--which for the most part are self-adhesive on their total contact surface to the skin--this primarily applies to the adhesive force and the cohesion. For instance, regions with an excessively high concentration may become too soft and therefore aggressively adherent, while regions with a low concentration possibly adhere poorly, consequently endangering the intense contact to the skin required for the function of the systems.